Discovery of New Non-Symmetrical Heterocyclic Pentanoid Derivatives Targeting Metastatic Triple-Negative Breast Cancer

  • Bioorg Med Chem Lett. 2025 Aug 1:123:130232. doi: 10.1016/j.bmcl.2025.130232.
Poh Yen Khor  1 ,  Johnson Stanslas  2 ,  Nurulfazlina Edayah Rasol  3 ,  Kok Meng Chan  4 ,  Phooi Yan Mock  5 ,  Kok Wai Lam  6
Affiliations
  • 1. Faculty Pharmacy and Health Sciences, Universiti Kuala Lumpur, Royal College of Medicine Perak, 30450 Ipoh, Perak, Malaysia. Electronic address: [email protected].
  • 2. Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
  • 3. Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia; Faculty of Applied Sciences, Universiti Teknologi MARA, 40450 Shah Alam, Selangor, Malaysia.
  • 4. Center for Toxicology and Health Risk Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
  • 5. Drugs and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, 50300 Kuala Lumpur, Malaysia.
  • 6. Drugs and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, 50300 Kuala Lumpur, Malaysia. Electronic address: [email protected].
PMID: 40209916 DOI: 10.1016/j.bmcl.2025.130232
Abstract

This study describes the synthesis and structure-activity relationship (SAR) analysis of non- symmetrical heterocyclic pentanoid derivative as potential anti-cancer agents. The lead compound, 5d, exhibited potent (IC50 = 0.38 ± 0.05 μM) and selective (Selectivity Index: 2-9) growth inhibitory effects on the metastatic triple-negative breast Cancer (TNBC) cells. Mechanistic studies revealed that 5d attenuates proteasomal degradation activity via the ubiquitin-proteasome pathway, leading to G2/M phase cell cycle arrest and the induction of apoptotic cell death.

Keywords
Anti-cancer; Proteasome; Ubiquitinated proteasome pathway.
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